Comparative evaluation of screening tools for sarcopenia in patients with axial spondyloarthritis

Sarcopenia is linked to chronic inflammation and muscle wasting. This research aims to compare the screening accuracy of tools for sarcopenia in axial spondyloarthritis (axSpA). A cross-sectional study involving 104 axSpA patients was conducted at Phramongkutklao Hospital between January 2020 and February 2021. Sarcopenia was diagnosed according to the AWGS 2019 criteria. Appendicular skeletal muscle mass was measured using DXA. SARC-F, SARC-CalF, and SARC-F+EBM, muscle strength, and physical performance were assessed. The screening tests were evaluated using ROC curves. The optimal cutoffs were identified with the Youden index. Most patients were male (74%), with a mean (SD) age and disease duration of 42.6 (12.22) and 8.3 (8.5), respectively. The prevalence of sarcopenia was 22.1%. The AUCs (95% CI) for calf circumference, SARC-F, SARC-CalF, SARC-F+EBM, handgrip strength, chair stand time, gait speed, and time and go test were 0.830 (0.734, 0.925), 0.509 (0.373–0.645), 0.782 (0.670–0.894), 0.856 (0.758–0.954), 0.710 (0.594–0.825), 0.640 (0.508–0.772), 0.689 (0.539–0.839), and 0.711 (0.576–0.846), respectively. The optimal cutoffs for SARC-F, SARC-CalF, and SARC-F+EBM were 1, 10, and 10, with sensitivity/specificity of 81.0%/29.7%, 90.5%/68.9%, and 77.3%/87.2%, respectively. Calf circumference, SARC-CalF, and SARC-F+EBM had the best performance to screen for sarcopenia in axSpA patients. Lowering the thresholds would potentially enhance the performances of SARC-CalF and SARC-F+EBM.

www.nature.com/scientificreports/axSpA patients have an elevated risk of developing sarcopenia due to the substantial burden of systemic inflammation.Additionally, these inflammatory cytokines contribute to increased muscle catabolism, prompting muscle loss, and down-regulation of anabolic hormones.Moreover, chronic inflammation stemming from ax-SpA can lead to chronic musculoskeletal pain, subsequently reducing physical activities and diminishing muscle utility.The prevalence of sarcopenia in axSpA was reported between 15 and 62% depending on the patients' characteristics, the diagnostic approaches and criteria, and the methods of skeletal muscle measurements 6 .Sarcopenia is associated with high disease activity, poor functioning, and low bone mineral density in axSpA patients 6 .
Recognizing and treating sarcopenia is important because of the associated adverse health outcomes, including disability, insulin resistance, falls, frailty, and mortality.Given the high prevalence of sarcopenia in axSpA patients, despite their relatively young age and the adverse health outcomes, screening and early diagnosis of sarcopenia are important.Our study is aimed at identifying the most appropriate screening tools for sarcopenia in axSpA patients.

Method
Between January 2020 and February 2021, a cross-sectional study involving 104 patients was conducted at Phramongkutklao Hospital in Bangkok, Thailand.The study's inclusion criteria required consecutive ax-SpA patients who met the 2009 Assessment of Spondyloarthritis International Society (ASAS) criteria, were at least 18 years old, and were willing to participate in the study.The exclusion criteria included having active cancer, pregnancy, breastfeeding, high-dose steroid use, an inability to undergo a physical test, and limitations regarding dual-energy X-ray absorptiometry (DXA), such as recent exposure to barium or radionuclides within the past 2 weeks.The study received approval from the Royal Thai Army Institutional Board Review under the reference R011h/63, and written informed consent was obtained from all participants prior to their participation.

Screening tools for sarcopenia
This study aimed to investigate the following screening tools for sarcopenia in patients with axial spondyloarthritis (axSpA).
1.The SARC-F is composed of five screening questions that assess muscle strength, walking ability, rising from a chair, climbing stairs, and the self-reported number of falls in the previous year.Each question can be answered on a scale from 0 to 2, resulting in a total score ranging from 0 to 10.A score equal to or greater than 4 is considered the cutoff for a positive screening test for sarcopenia 7 .2. SARC-CalF is comprised of the SARC-F questionnaire along with an additional 10 points assigned for having a maximum calf circumference equal to or less than 34 cm for men and 33 cm for women.The SARC-CalF score has a range of 0 to 20, and a score equal to or greater than 11 is considered the cutoff for a positive screening test for sarcopenia 8 .3. SARCF + EBM is composed of the SARC-F questionnaire and incorporates scores based on age and BMI assessments.For age, patients aged < 75 years old were assigned a score of 0, while patients ≥ 75 years old received a score of 10.Regarding BMI, patients with a BMI > 21 kg/m 2 were assigned a score of 0, whereas those with a BMI ≤ 21 kg/m 2 received a score of 10.The SARC-F + EBM score has a range of 0-30, and a score equal to or greater than 12 is utilized as the cutoff for a positive screening test for sarcopenia 9 .4. Handgrip strength assessment was assessed by a digital hand dynamometer set at the fifth strength level.
Initially, participants used their dominant hand while seated, maintaining a 90-degree elbow flexion, and performed three grip tests.The best performance from these tests was recorded in kilograms.The thresholds specified in the AWGS 2019 guidelines for categorizing low handgrip muscle strength stand at < 28.0 kg for men and < 18.0 kg for women 4 .These cutoff values were derived from normative data gathered from a combined dataset of eight cohorts in Asia 10 . 5. The chair stand time records the time needed to complete five repetitions of standing up and sitting down in a chair, with the measurement recorded in seconds.A completion time of 12 s or more is considered the cutoff for low physical performance 4 .6.The gait speed test measures the time required for participants to walk 6 m at a standard pace, with two trials conducted, and then calculates the resulting average in meters per second.A gait speed of less than 1.0 m per second in the 6-m walk is considered the cutoff for low physical performance 4 .7. The time up-and-go test measures the time from when participants initially sit in the chair to the moment they stand up, walk three meters forward at their usual walking speed, turn around at a designated marker, walk back to the chair, and sit down again.The time up-and-go test of more than 10 s is considered the cutoff for low physical performance 11 .However, the time up-and-go test was not included in the diagnosis of sarcopenia by the AWGS 2019 criteria.

Definition of sarcopenia
Sarcopenia was diagnosed following the AWGS 2019 clinical research setting pathway algorithm 4 .Muscle strength and physical performance were assessed by the same investigation (NK).Appendicular skeletal muscle mass (ASM) was measured by anteroposterior dual-energy X-ray absorptiometry (DXA), using the GE-Lunar iDXA (#210754) and GE-Lunar DPX Duo densitometer (GE Healthcare, Madison, WI, USA).The lean mass of the arms and legs was considered equivalent to the skeletal muscle mass.To determine the skeletal muscle mass index (SMI), the lean mass was divided by height squared (kg/m 2 ).The appendicular SMI was calculated as the sum of arm and leg SMIs (kg/m 2 ).According to the AWGS 2019 criteria for diagnosing sarcopenia, individuals are categorized as having low muscle mass if their SMI falls below 7.0 kg/m 2 for men and 5.4 kg/m 2 for women 4 .

Result
This study comprised 104 ax-SpA patients, with the majority being male (74%).The patients were presented with a mean (SD) age and disease duration of 42.6 (12.2) and 8.3 (8.5) years, respectively.The prevalence of sarcopenia, severe sarcopenia, and possible sarcopenia in axSpA patients were 22.1% (23/104), 4.8% (5/104), and 85.6% (89/104), respectively.There were two patients who could not perform a chair stand time test, and one patient could not perform a time up and go test because of severe low back pain.Extra-articular manifestations, such as anterior uveitis and psoriasis, were observed in 5.8% and 1.5% of the ax-SpA patients, respectively.Regarding current treatment, non-steroidal anti-inflammatory drugs (NSAIDs) were prescribed to 58 patients (55.8%), glucocorticoids to 7 patients (6.7%), and conventional synthetic diseasemodifying antirheumatic drugs (csDMARDs) to 78 patients (75%).Methotrexate and sulfasalazine were the most commonly prescribed csDMARDs.Additionally, 26 patients (25%) were receiving biologic agents, with anti-tumor necrosis factor (anti-TNF) agents being the most frequently used (23 patients), while only three patients were receiving anti-interleukin-17 (anti-IL-17) agents.
The mean Ankylosing Spondylitis Disease Activity Score (ASDAS) was 2.6 (SD = 1.2), with 40 patients having high disease activity and 26 patients having very high disease activity.The mean Bath Ankylosing Spondylitis Functional Index (BASFI) score, which assesses functional impairment, was 2.4 (SD = 2.4).Significant functional limitations (BASFI > 4) were found in 20 patients (19%).The details of patients' characteristics and the differences between axSpA patients with and without sarcopenia were described in the previous report 6 .

Discussion
The prevalence of sarcopenia is considerable, affecting approximately one-fifth (22.1%) of axSpA patients.Furthermore, sarcopenia was reported to be associated with poor function as measured by BASFI score 6 , underscoring the importance of screening for sarcopenia in axSpA patients.The SARC-F questionnaire is straightforward and stands as a convenient tool for routine use in rheumatology clinics.With good reliability, it has been translated into numerous languages as well as validated for the uses in various diseases and patient populations 12 .It is recommended by EWG-SOP2 and AWGS 2019 recommendations as the screening tool in the sarcopenia casefinding strategy.However, the present study reveals that SARC-F has low sensitivity (28.6%) and low diagnostic accuracy (AUC 0.509) in identifying sarcopenia among axSpA patients.These findings are aligned with prior  www.nature.com/scientificreports/studies conducted across various populations, including systemic sclerosis 13 , chronic kidney disease patients 14 , and the elderly 15 .The characteristics of a good screening test depend on the prevalence of the disease.In the case of diseases with low prevalence, the screening test should exhibit high specificity and PPV.Conversely, for more common diseases, the screening test should prioritize high sensitivity and NPV.Given the common occurrence of sarcopenia, an ideal screening modality should emphasize high sensitivity and NPV.Consequently, SARC-F might not be an optimal tool as a screening test for identifying sarcopenia in axSpA patients.To enhance the sensitivity of SARC-F, several strategies have been proposed.First, the cutoff value of SARC-F can be adjusted.Lowering the cutoff of the SARC-F score to ≥ 1 increases the sensitivity and AUC 16 with acceptable specificity 17,18 .
The second strategy involves integrating SARC-F with other variables such as calf circumference, age, or BMI.The present studies revealed that SARC-CalF and SARCF + EBM significantly improved sensitivity and diagnostic accuracy as compared to SARC-F alone.Consistent with our findings, prior studies reported that SARC-CalF significantly improves the sensitivity and overall diagnostic accuracy of SARC-F for screening sarcopenia in community-dwelling older adults as well as nursing home residents 19 , hemodialysis patients 20 , diabetes mellitus patients 21 , and advanced cancer patients 22 , regardless of which diagnostic criteria were used (EWGSOP2, AWGS 2019, International Working Group on Sarcopenia, and Foundation for the National Institutes of Health).Additionally, in patients experiencing chronic musculoskeletal pain, both SARC-F and SARC-CalF exhibited significant correlations with pain-related disability.Both tools proved reliable for screening sarcopenia in chronic musculoskeletal pain; however, SARC-CalF demonstrated higher reliability than SARC-F 23 .
SARC-F + EBM was initially proposed and validated by Kurita et al. in 2019 against AWGS and EWGSOP2 criteria for sarcopenia in 959 adult patients with musculoskeletal diseases scheduled for spinal surgery, knee, or hip replacement therapy 9 .Given that axSpA patients often present with hip and/or knee arthritis and chronic low back pain, resembling the cohort from the original SARC-F + EBM study, it is intriguing to assess its potential as a screening tool in axSpA.Our findings indicated a significant improvement in the sensitivity and overall diagnostic accuracy of SARC-F + EBM over SARC-F alone for sarcopenia screening.However, the sensitivity of SARC-F + EBM in this study was 40.9%, contrasting with the study by Kurita et al., which reported a higher sensitivity of 77.8%.This discrepancy in sensitivity could be attributed to the age difference among study participants, as the additional 10 score of SARC-F + EBM is assigned for ages ≥ 75 years old.Notably, axSpA patients in our study were younger compared to those with degenerative diseases in the other study, suggesting the necessity to consider a lower cutoff for SARC-F + EBM in axSpA patients, potentially below 12.Moreover, it's crucial to note the difference in the criteria used for diagnosing sarcopenia; our study employed AWGS2 criteria, while Kurita et al. used AWGS.Given the recent introduction of SARC-F + EBM, its validation has been limited to a few studies and specific patient populations.
The third strategy is to use calf circumference independently as an alternative to SARC-F and its modified versions for sarcopenia screening.This study demonstrated that the calf circumference exhibits high sensitivity, negative predictive value, and diagnostic accuracy as indicated by the AUC.Hence, it could serve as an effective screening tool for sarcopenia in axSpA patients.Low calf circumference has been reported to be correlated with low skeletal muscle mass, low muscle strength 24 , low physical performance 24 , sarcopenia 25 , and increased mortality 25 in different settings (community, hospital, and nursing home settings) and various patient populations (parkinsonism, stroke, chronic liver diseases, and interstitial lung diseases) 26 .Despite these advantages, limitations exist, notably the variability in calf circumference measurements and the absence of standardized cutoff values tailored for diverse patient demographics such as age or ethnicity.Nevertheless, the AWGS 2019 recommends measuring calf circumference alone as one of the tools for the initial screening of sarcopenia 4 .
The diagnostic performance of the screening tools is reliant upon the chosen cutoff value.The cut-off SARC-CalF was first investigated in community-dwelling elderly aged 60 years or older in Brazil with a prevalence of sarcopenia of 8.3%.The best cutoff for sarcopenia is over 11, which results in the Youden index of 0.5 and the AUC of 0.736 8 .Conversely, in a study among community-dwelling older adults aged 75 years and older in Japan, where sarcopenia prevalence was 8.3%, the identified best cutoff for sarcopenia was over 7, exhibiting high sensitivity (94.7%), specificity (92.3%), and an AUC of 0.98 27 .In the present study, featuring a prevalence of sarcopenia of 22.1%, the optimal SARC-CalF cutoff with the highest Youden index was 10.Variations in cutoff values could be attributed to differences in patient populations, particularly age and sarcopenia prevalence, where lower prevalence necessitates higher cutoff scores.The best cutoff score for SARC-F + EBM from the present study is 10, which is lower than the cutoff from the original study at 12 9 , and the difference could likely be due to the younger age of axSpA patients in this study.
This study has several limitations.Firstly, it features a relatively small sample size, focusing exclusively on Thai or Asian participants.Therefore, the findings of this study need validation through larger-scale studies involving diverse ethnicities.Secondly, unlike rheumatoid arthritis, the implications of sarcopenia in axSpA have not been well established.Thirdly, universal sarcopenia screening is currently not recommended due to the absence of an identified or validated appropriate test.Furthermore, it remains to be demonstrated whether screening would yield health benefits that outweigh the associated costs.

Conclusions
To the best of our knowledge, this study is the first to evaluate various tools for sarcopenia screening in axSpA.We found that calf circumference, SARC-CalF, and SARC-F + EBM had the best performance for identifying sarcopenia in axSpA patients.Our findings align with the AWGS 2019 guideline, endorsing sarcopenia case-finding strategies through the evaluation of calf circumference, SARC-F, or SARC-CalF, supplemented by SARC-F + EBM.In contrast, EWG-SOP2 recommends solely SARC-F, or clinical suspicion, for screening in the https://doi.org/10.1038/s41598-024-65120-2

Figure 1 .Table 3 .
Figure 1.Receiver operating characteristic (ROC) curve analysis of sarcopenia screening tests in relation to sarcopenia defined according to AWGS 2019 criteria in axial spondyloarthritis patients.

Table 1 .
Table 3 displays the performance characteristics of SARCF, SARCF + EBM, and SARC-CalF, including sensitivity, specificity, false positive rate, and the Youden index.Sarcopenia assessments of axial spondyloarthritis patients with and without sarcopenia.a Two-sample Wilcoxon rank-sum test.b Pearson chi-square test.c Exact probability test.d Independent t-test.
Significantly different with Gait speed 6 m walk (p < 0.05).B p-value < 0.05 by the DeLong method.b Significantly different with Calf circumference (p < 0.05).